This application is a 371 of PCT/JP99/04868 filed Aug. 9, 1999.
The present invention relates to a carboxylic acid derivative and a peroxisome proliferator activated receptor regulator containing carboxylic acid derivative as active ingredient.
More particularly, the present invention relates to a compound of formula (I) 
(wherein all symbols are the same meanings as hereinafter described), a non-toxic salt thereof and a hydrate thereof, a process for the preparation thereof and a peroxisome proliferator activated regulator containing thereof as active ingredient.
Recently in the study of transcription factors concerned with marker genes expression in adipocytes differentiation, peroxisome proliferator activated receptor (abbreviated as PPAR hereinafter), which is one of intranuclear receptors, has been focused. cDNAs of PPAR were cloned from various kinds of animals, and plural isoform genes were found, particularly in mammals three types of isoforms (xcex1,xcex4,xcex3) are known (see J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Gene Expression,. 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol. Endocrinology., 6, 1634 (1992)). PPARxcex3 isoform is predominantly expressed in adipose tissues, immune cells, adrenal gland, spleen, small intestine. PPARxcex1 isoform is mainly expressed in adipose tissue, liver, retina, and PPARxcex4 isoform is widely expressed without specificity for tissue (see Endocrinology., 137, 354 (1996)).
On the other hand, the following thiazolidine derivatives are known as agents for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and are hypoglycemic agents which are used for the improvement of hyperglycemia in the patients suffering from diabetes. They are also effective for the improvement of hyperinsulinemia, glucose tolerance and decrease of serum lipid and therefore they are thought to be considerably hopeful as agents for the treatment of insulin resistance. 
One of the target proteins in the cells of these thiazolidine derivatives is exactly PPARxcex3 and it is resolved that they enhance the transcription activity of PPARxcex3 (see Endocrinology., 137, 4189 (1996); Cell., 83, 803 (1995); Cell., 83, 813 (1995); J. Biol. Chem., 270, 12953 (1995)). Therefore, a PPARxcex3 activator (agonist) which enhances its transcription activity is thought to be hopeful as a hypoglycemic agent and/or a hypolipidemic agent. Furthermore, since a PPARxcex3 agonist is known to promote the expression of PPARxcex3 protein itself (Genes and Development., 10, 974 (1996)), an agent which increases the expression of PPARxcex3 protein itself as well as PPARxcex3 activating agent is also thought to be clinically useful.
Among all of nuclear receptors, PPARxcex3 is related to adipocytes differentiation (see J. Biol. Chem., 272, 5637 (1997) and Cell., 83, 803 (1995)). It is known that thiazolidine derivatives which activate this receptor promote adipocytes differentiation. Recently it was reported that thiazolidine derivatives increase fat mass and cause man to gain weight and to become obese (see Lancet., 349, 952 (1997)). Therefore, it is also thought that antagonists which inhibit PPARxcex3 activity and agents that decrease the expression of PPARxcex3 protein itself are also clinically applicable. On the other hand, a compound that phosphorylates PPARxcex3 protein and decreases its activity is reported (Science., 274, 2100 (1996)). This implies that an agent which does not bind on PPARxcex3 protein as a ligand, but inhibits its activity is also clinically applicable.
From these, PPARxcex3 activators (agonists) and PPARxcex3 regulators for its expression that can increase the expression of the protein itself are expected to be useful as hypoglycemic agents, hypolipidemic agents, and agents for prevention and/or treatment of diseases associated with metabolic disorders such as diabetes, obesity, syndrome X, hypercholesterolemia and hyperlipoproteinemia etc., hyperlipidemia, atherosclerosis, hypertension, circulatory diseases and overeating etc.
On the other hand, antagonists that inhibit the transcription activity of PPARxcex3 or PPARxcex3 regulators that inhibit the expression of the protein itself are expected to be useful as hypoglycemic agents and agents for prevention and/or treatment of diseases associated with metabolic disorders such as diabetes, obesity and syndrome X etc., hyperlipidemia, atherosclerosis, hypertension and overeating etc.
The following fibrate compound (e.g. chlofibrate) is known as a hypolipidemic agent. 
And, it is also resolved that one of the target proteins in the cells of fibrate compounds is PPARxcex1 (See Nature., 347, 645 (1990); J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Biochemistry., 32, 5598 (1993)). From these facts, PPARxcex1 regulators which can be activated by fibrate compounds are thought to have a hypolipidemic effect, and so they are expected to be useful as agents for prevention and/or treatment of hyperlipidemia etc.
Besides, it has been recently reported that PPARxcex1 possesses anti-obese activity in the specification of WO 9736579. In addition, it was reported that the elevation of high density lipoprotein (HDL) cholesterol level and the reduction of low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol and triglyceride levels were induced by activation of PPARxcex1 (J. Lipid Res., 39, 17 (1998)). It was also reported that composition of fatty acids in blood, hypertension and insulin resistance were improved by administration of bezafibrate which is one of fibtrate compounds (Diabetes., 46, 348 (1997)).
Therefore, agonists that activate PPARxcex1 and PPARxcex1 regulators that promote expression of PPARxcex1 protein itself are useful as hypolipidemic agents and agents for treatment of hyperlipidemia, and are expected to have HDL cholesterol level-elevating effect, LDL cholesterol and/or VLDL cholesterol levels-lowering effect, inhibition on the progress of atherosclerosis and anti-obese effect. Therefore, they are thought to be hopeful agents for the treatment and/or prevention of diabetes as hypoglycemic agents, for the improvement of hypertension, for the relief from risk factor of syndrome X and for the prevention of occurrence of ischemic coronary diseases.
On the other hand, few reports are found on ligands that activate PPARxcex4 significantly or on biological activities associated with PPAR xcex4. PPARxcex4 is sometimes called PPARxcex2, or it is also called NUC1 in human. Until now, as for activity of PPARxcex4, it is disclosed in the specification of WO 9601430 that hNUC1B (PPAR subtype whose structure is different from that of human NUC1 in one amino acid) inhibited the transcription activities of human PPARxcex1 and thyroid hormone receptor. Recently in the specification of WO 9728149, it was reported that the compounds, which possessed high affinity to PPARxcex4 protein and which could activate PPARxcex4 significantly (i.e. agonists) were found out and that they had HDL (high density lipoprotein) cholesterol level-elevating activity. Therefore, agonists that can activate PPARxcex4 are expected to have HDL cholesterol level-elevating effect, and so they are expected to be useful for the inhibition on the progress of atherosclerosis and treatment thereof, as hypolipidemic agents and hypoglycemic agents, for the treatment of hyperlipidemia, as hypoglycemic agents, for the treatment of diabetes, for the relief from risk factor of syndrome X, and for the prevention of occurrence of ischemic coronary diseases.
As for PPAR regulators, the following compounds were reported besides the above-mentioned thiazolidine derivatives and fibrate compounds.
For example, in WO9731907, it is disclosed that the compounds of formula (A) 
(wherein AA is phenyl, in which the said phenyl may be substituted with one or more substituent(s) selected from group consisting of halogen, C1-6 alkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, nitrile or xe2x80x94NR7AR8A (R7A and R8A each independently, is hydrogen or C1-3 alkyl);
BA is (5- or 6-membered heterocyclic ring containing at least one hetero atom selected from O, N and S)xe2x80x94C1-6 alkylene-, in which the said heterocyclic ring may be substituted with C1-3 alkyl;
AlkA is C1-3 alkylene;
R1A is hydrogen or C1-3 alkyl;
ZA is xe2x80x94(C1-3 alkylene)phenyl or xe2x80x94NR3AR4A)
or pharmaceutically acceptable salts thereof possess PPAR xcex3 agonist activity (the necessary parts in explanation of symbols are shown).
On the other hand, in JP-A-9-323982, it is disclosed that the propionic acid derivatives of formula (B) 
(wherein RB is 
or 
(wherein Rxe2x80x2B is substituted or unsubstituted aromatic hydrocarbon, substituted or unsubstituted aliphatic hydrocarbon ring, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted condensed heterocyclic ring, R5B is lower alkyl), R4B is hydrogen or lower alkyl, R6B is hydrogen or R6B and R9B taken together form double bond, R7B is hydrogen, hydroxy, carboxy, acyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted aralkyloxycarbonyl or xe2x80x94YBxe2x80x94R8B (in which YB is xe2x80x94NHxe2x80x94 or O, R8B is substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl), R9B is hydrogen, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkoxycarbonyl, R10B is hydroxy, substituted or unsubstituted amino, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryloxy or substituted or unsubstituted aralkyloxy)
or pharmaceutically acceptable salts thereof possess hypoglycemic action and hypolipidemic action. In addition, JP-A-8-325264, JP-A-8-325250, WO9638415 and WO9800137 have also disclosed that analogous compounds possess hypoglycemic action and hypolipidemic action.
In JP-A-5-507920, it is disclosed that the compound of formula (C) 
(wherein Ac is 
nC is 0 or 1;
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xe2x80x83represents bond or not represents bond,
RC is C1xcx9cC8 alkyl, C3xcx9cC7 cycloalkyl, C3xcx9cC8 alkenyl, C3xcx9cC8 alkynyl, phenyl,
C7xcx9cC8 phenylalkyl, C2xcx9cC8 alkanoyl, or one of above groups substituted by one or two of C1xcx9cC3 alkyl, trifluoromethyl, hydroxy, C1xcx9cC3 alkoxy, fluoride or chloride;
XC is S, O, NR2C, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94 or xe2x80x94Nxe2x95x90CH;
R2C is hydrogen, C1xcx9cC3 alkyl, pheny or benzyl;
YC is CH or N;
ZC is hydrogen, C1xcx9cC7 alkyl, C3xcx9cC7 cycloalkyl, phenyl, or phenyl substituted by one or two of C1xcx9cC3 alkyl, trifluoromethyl, C1xcx9cC3 alkoxy, phenyl, phenoxy, benzyl, benzyloxy, fluoride or chloride;
XC is O, S, SO or SO2;
YC is hydroxy, C1xcx9cC3 alkoxy;
ZC is hydrogen or C1xcx9cC3 alkyl.) possess hypoglycemic action and hypolipidemic action.
J. Med. Chem., 39, 3897 (1996) have also disclosed that analogous compounds possess hypoglycemic action and hypolipidemic action, the compound of formula (D) is disclosed. 
As the result of energetic investigations in order to find compounds possessing regulating action on PPAR, the present inventors have found that the purpose has been accomplished by the compound of formula (I) and have completed the present invention.
The present invention relates to
(1) a compound of formula (I) 
xe2x80x83(wherein R1 independently, is hydrogen, C1xcx9c8 alkyl, halogen, C1xcx9c4 alkoxy, C1xcx9c4 alkoxy, C1xcx9c4 alkylthio, nitro, NR4R5 (in which R4 and R5 each independently, is C1xcx9c4 alkyl.), cyano, trifluoromethyl, trifluoromethyloxy, carbocyclic ring or hetero ring (carbocyclic ring and hetero ring are optionally substituted by group selected from C1xcx9c4 alkyl, C1xcx9c4 alkoxy, halogen or trifluoromethyl.),
R2 is hydrogen, C1xcx9c8 alkyl, halogen, C1xcx9c4 alkoxy, C1xcx9c4 alkylthio, nitro,
NR4R5 (in which R4 and R5 each independently, is C1xcx9calkyl.), cyano, trifluoromethyl or trifluoromethyloxy,
R3 is hydrogen or C1xcx9c4 alkyl,
X1 is xe2x80x94Nxe2x80x94 or xe2x80x94CHxe2x80x94,
X2 and Y each independently, is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR6xe2x80x94 (in which R6 is hydrogen or C1xcx9c4 alkyl.),
Z is xe2x80x94Oxe2x80x94 or xe2x80x94S(O)pxe2x80x94 (in which p is 0, 1 or 2),
R7 and R8 each independently, is hydrogen or C1xcx9c4 alkyl, or R7 and R8 taken together with carbon atom to which is attached represents C3xcx9c7 cycloalkylene, 
xe2x80x83is carbocyclic ring or hetero ring, 
xe2x80x83is double bond or triple bond,
m and n each independently, is 1xcx9c3.) a non-toxic salt thereof, or a hydrate thereof,
(2) a peroxisome proliferator activated receptor regulator containing a compound of formula (I), a non-toxic salt thereof, or a hydrate thereof as active ingredient, and
(3) a process for the preparation of a compound of formula (I).